1. Field of the Invention
The present invention relates to a compound synthesis method for nuclear medicine imaging agent for HDAC (histone deacetylase) inhibitor, in particular, to compounds of imaging agent that includes HDAC inhibitor BNL-26 (C22H23N3O) and a plurality of its analogue compounds to be labeled with radionuclide F-18, and to use of pyridine to substitute the benzene ring of the BNL-26 structure and synthesizing with other substituent to produce a series of novel HDAC inhibitors for diagnosing cancer and Alzheimer's disease.
2. Description of the Related Art
Histone deacetylase inhibitors (HDAC inhibitors or HDACi) are medication for controlling histone deacetylase in the human body and being used to treat cancer and neurodegeneration disease by the medical research in medical industries. These specific mechanisms of inhibitor are disclosed in the characterization of genomics approaches presented in the literature, for example, Richon et al. found that HDAC inhibitors may be used to regulate the tumor suppression function of P53 through introducing cyclin-dependent kinase inhibitor P21(WAF1).
Conventional studies about cancer and development dysplasia of organs like colon, rectum, cervix, stomach, and prostate have not been a satisfactory outcome. Besides, the research of natural aging indicates that cerebral atrophy is an early sign of neurodegeneration related to cognitive deficit and loss of memory, and dementia like Alzheimer's disease usually leads the patient of such disease to an unrecoverable situation for unknown causes and lacking of a measure of early diagnosis of Alzheimer's disease. And early discovery, diagnosis, and curing of cancer and Alzheimer's disease depend on diagnostic methods is still in vain. In the prior art, U.S. Pat. No. 7,868,205, it disclosed that o-amino benzamide HDAC inhibitors had a much bigger but flat aromatic and heteroaromatic substituents such as phenyl, furyl, thienyl and the like para to the amino moiety. Also, U.S. Pat. No. 9,108,943 disclosed studies of a series of photoreactive potent and selective HDACs 1 and 2 benzamide based probes.
According to research in cancer and development dysplasia of body organs, over-expression of histone deacetylase 2 (HDAC-2) does exist in both cases and in many cases of those diseases, such as colon, rectum, cervix, stomach, and prostate etc. Furthermore, the research in recent years also pointed out that chromatin modification in the brain cells is related to the memory formation which is influenced intensely by histone deacetylase, for example, a mouse with abnormal secretion of histone deacetylase enzyme could lose part of memory as same as the symptom of Alzheimer's disease. Thus, dosing histone deacetylase inhibitors will be a new hope to the treatment of cancer and Alzheimer's disease.
HDAC inhibitors have been a hot spot of medication research as a targeted anti-tumor medication. The existing HDAC inhibitors are mainly divided into four categories according to structure, comprising: (a) hydroxamic acids, suchlike Vorinostat; (b) cyclic tetrapeptide, suchlike Romidepsin (FK228) and depsipeptide; (c) benzoylamide, suchlike MS-275 and SC-027; (d) short-chain fatty acid, suchlike valproic acid and butyrate. The efficacies of HDAC inhibitors for treating hematologic malignancies and solid tumors are confirmed both in vivo and vitro experiments. The vitro experiment confirmed that HDAC inhibitors exhibits good anti-tumor effect to the tumor cell of bladder, bone, breast, uterus, central nervous system, esophagus, lung, ovary, pancreas, or prostate by tumor cell apoptosis, proliferation inhibition and cell cycle arrest, and many types of HDAC inhibitors are entering phase I or II or III of clinical study for their multiple paths and high efficiencies for anticancer.
Vorinostat (suberoylanilide hydroxamic acid, SAHA) and Romidepsin (cyclic peptide) are approved by FDA to be listed for applying to cutaneous T-cell lymphoma (CTCL) and the application of the treatment of solid tumor is also in clinical trials. The benzoylamide HDAC inhibitors chidamide developed by Chipscreen Ltd. is approved by FDA for clinical research in USA to confirm that the new type HDAC inhibitors in small doses and low concentration can induce tumor cell differentiation and selective apoptosis for anti tumor proliferation and be non-toxic to normal cells.
By analysis of tumor diagnoses in identification of whether a tumor exists, the nature of tumors, benign or malignant ones, phase of tumor stage and metastasis are all very important, it revealed that most tumors are often found lately, and at the time it has already caused damage to one or more functions of vital organs, and even has been transferred to the entire body. Therefore, the key question is how to treat tumor in early detections, but detection of tumors in earlier stage is still very difficulty.
Diagnosis of Alzheimer's disease (referred to as AD) includes basic check neuropsychological tests, blood routine, biochemical test of liver and kidney functions, vitamin B12 level, thyroid function, syphilis serology, and brain computed tomography or magnetic resonance angiography. High order PET positron imaging diagnostic methods exploiting amyloid hypothesis as the theoretical basis for drugs include F-18-AV45 and F-18-PIB two kinds, whereas the microtubule associated protein hypothesis (Tau hypothesis) as the theoretical basis for drug is not yet available.
Clinical diagnosis with imaging inspection includes X-ray examination, ultrasonography, magnetic resonance imaging, X-ray tomography (abbreviated CT) and radioisotope examination. Early diagnosis of tumor and Alzheimer's disease has a role of important significance, because only a early diagnosis and treatment can get better result of treatment. However, due to various objective and subjective reasons, the majority of patients in the treatment or diagnosis of tumors that already advanced in midterm or later, and the treatment effect is not satisfactory in this case. Although the diagnosis method of tumor is developing rapidly, but many tumor screening methods are not effective enough, and it takes that tumors need to be of 1˜1.5 cm in diameter size before it can be clearly displayed in an imaging inspection.
A general blood test accuracy is insufficient, for example, a prostate-specific antigen (PSA) is a glycoprotein. This antigen can only be produced by prostate cells, when a prostate disease occurs, such as prostate tumor, a prostate hyperplasia cell will produce an excess of PSA that leads to the PSA level in the blood increases. Doctors may analyze blood PSA levels to determine the possibility of patients suffering from a prostate tumor. There are various factors leading to elevated PSA, such as prostate infection and benign prostate hyperplasia. Moreover, not all prostate cancer patients exhibited elevated PSA, thus a PSA test result can not be confirmed for a candidate of prostate cancer patient. Diagnosis of Alzheimer's disease with the latest PET drugs F-18-AV45 and F-18-PIB, the imaging of PET can only be diagnosed whether an Alzheimer's disease exists, however, human aging phenomenon also reveals an identical reaction with the same image, and thus it is difficult to confirm that a patient is suffering from Alzheimer's disease with the image presented.